This project proposes to closely investigate the role of the mu-opiate receptor in association with antidepressant response and Major Depressive Disorder (MOD). The first specific aim describes how functional analyses will follow up on a previously detected association between genetic polymorphisms and antidepressant response. One of the variants is located in a coding region of an alternatively spliced isoform of the mu-opioid receptor (OPRM1) gene, resulting in an amino acid change and potentially has biological significance. Expanding the findings of a pure association study to one that involves functional analysis of associated variants will broaden the biological implications of this study. The results of these studies may potentially demonstrate that individuals with certain OPRM1 genotypes may respond to the antidepressant, citalopram, better than alternative genotypes. The second specific aim will determine if the previously associated variants are truly those causing the detection signal. It is possible that the variant was detected because it is linked with another actual causal variant, and the only way to determine this is to test surrounding variant by direct sequencing. Thirdly, this project will test for association with variants in the OPRM1 gene and Major Depressive Disorder. The same variants that were analyzed for association with antidepressant response will be investigated for association with the disorder, utilizing samples from patients with MOD, compared to those without. Knowing if OPRM1 contributes to the genetic basis of MOD, will allow for identification of known genetic risk factors, advancing our knowledge of the etiology of MDD. [unreadable] [unreadable] To individualize medicine, it would be extremely beneficial to know which patients would respond to, or be tolerant to particular pharmaceutical antidepressant treatments, based on their genetic constitution alone. If treatment could be streamlined by knowing the genetic risk for antidepressant response, recovery from MDD would be transformed, and a significant decrease in the length of time spent suffering would provide an enormous benefit to society. [unreadable] [unreadable] [unreadable]